Differential role of GDNF and NGF in the maintenance of two TTX-resistant sodium channels in adult DRG neurons

Following sciatic nerve transection, the electrophysiological properties of small dorsal root ganglion (DRG) neurons are markedly altered, with attenu ation of TTX-R sodium currents and the appearance of rapidly repriming TTX- S currents. The reduction in TTX-R currents has been attributed to a down-r egulation of sodium channels SNS/PN3 and NaN. While infusion of exogenous N GF to the transected nerve restores SNS/PN3 transcripts to near-normal leve ls in small DRG neurons, TTX-R sodium currents are only partially rescued. Binding of the isolectin IB4 distinguishes two subpopulations of small DRG neurons: IB4(+) neurons, which express receptors for the GDNF family of neu rotrophins, and IB4(-) neurons that predominantly express TrkA. We show her e that SNS/PN3 is expressed in approximately one-half of both IB4(+) and IB 4(-) DRG neurons, while NaN is preferentially expressed in IB4(+) neurons. Whole-cell patch-clamp studies demonstrate that TTX-R sodium currents in IB 4(+) neurons have a more hyperpolarized voltage-dependence of activation an d inactivation than do IB4(-) neurons, suggesting different electrophysiolo gical properties fur SNS/PN3 and NaN. We confirm that NGF restores SNS/PN3 mRNA levels in DRG neurons in vitro and demonstrate that the trk antagonist K252a blocks this rescue. The down-regulation of NaN mRNA is, nevertheless , not rescued by NGF-treatment in either IB4(+) or IB4- neurons and NGF-tre atment in vitro does not significantly increase the peak amplitude of the T TX-R current in small DRG neurons. In contrast, GDNF-treatment causes a two fold increase in the peak amplitude of TTX-R sodium currents and restores b oth SNS/PN3 and NaN mRNA to near-normal levels in IB4(+) neurons. These obs ervations provide a mechanism for the partial restoration of TTX-R sodium c urrents by NGF in axotomized DRG neurons, and demonstrate that the neurotro phins NGF and GDNF differentially regulate sodium channels SNS/PN3 and NaN. (C) 1999 Elsevier Science B.V. All rights reserved.